The androgen receptor (AR) plays an integral role in primary and secondary male sexual development. While abnormalities resulting in an attenuation of the AR response to endogenous hormones (testosterone and its reduced form, 5α-dihydrotestosterone or DHT) produce male infertility and feminization, excessive stimulation of AR can also result in pathologies. The most commonly presented diseases of this type are prostate cancer and the related, but benign, prostatic hyperplasia. Both of these diseases are responsive to endocrine-based treatments that attempt to suppress tumor/prostate growth either by direct administration of an AR antagonist or by ‘chemical castration’ techniques that result in decreased gonadal production of the endogenous agonist, testosterone.
Prostate tumors treated with current clinically-applied antiandrogens generally develop resistance to these drugs over the course of months to a few years; at this point the cancer will continue to progress despite administration of the compound. The major benefit of the cyclobutane-core AR inhibitors (CB) is their ability to inhibit activation of AR under cellular conditions that are resistant to treatment using current clinically-available antiandrogens (i.e., flutamide, bicalutamide, nilutamide, enzalutamide, and cyproterone acetate). Consequently, the CB antiandrogens could either be used as a first line hormone therapy for prostate cancer (usually post radiation and/or surgery), or as a second line therapy after an initial course of antiandrogen therapy fails.
Initial cell-based results suggest that the CB antiandrogens may prove especially efficacious in those patients with certain AR point mutations, arising after initial treatment with an antiandrogen. Most notable among these is the mutation known as the LNCaP mutation, T877A, which is estimated to appear in as many as 30% of prostate cancer patients previously treated with flutamide. As such, this drug may prove to be a viable selective, targeted therapy for patients having this specific mutation, allowing for successful treatment of the cancer with minimal disruption of the natural hormonal actions of the wild type androgen receptors present in non-cancerous tissues. This drug may provide similar selective, targeted therapy for patients having other point mutations in AR that confer resistance to other AR antagonists. As far as we are aware, this form of selective, targeted hormonal therapy has not been considered before: it has novelty and the potential of significantly reducing the side effects (impaired sexual activity, muscle wasting, etc.) associated with current prostate cancer hormone therapy in this select subset of patients.